16, 17-oxido-pregnane-3alpha-ol-3, 20-dione



United States Patent dation of 20-keto-16-pregnenes.

Of the numerous steroids obtained from the adrenal cortex, those whichpossess a 17a-hydroxy-20-keto structure are of special interest becauseof their provenor possible value in the treatment of rheumatoidarthritis and other disorders. Among these may bementioned KendallsCompound E (Cortisone), Reichsteins Compound S,17a-hydroxy-progesterone, and 17-hydroxy-corticosterone. Others, such asA -pregnene-3p,17a,2l-triol-ZO- one, are also of interest.

Since the supply of those naturally-occurring 17ahydroxy steroids islimited, their partial synthesis from sterols, bile acids and genins isbeing studied in many laboratories. One of the proposed methods involvesthe preparation of 16-dehydro-20-keto compounds, which are thenconverted to 17a-hydroxy compounds via 16,17- epoxides. 2

It is known that these epoxides can be made by treatment with perbenzoicacid. But where there are double bonds elsewhere in the ring, such as atthe 5-6 position, epoxidation also takes place there. Also, theformation of lactones occurs in such compounds as the 3-keto steroids asreported by Burckhardt and Reichstein, Helv. 25, 1434 (1942). Theseauthors, however, state unequivocably that 3a-acetoxy-12-keto-cholanicacid does not react with perbenxoic acid under the conditions employed.Moreover, Sarett, J. A. C. S. 69, 2899 (1947), reported a yield of 85%of 17-acetoxy-1l-keto-S-acetoxyetiocholane by the oxidation of3-acetoxy-11,20-diketo pregnane with perbenzoic acid. The results ofSarett and of Burckhardt and Reichstein would suggest that no lactoneformation took place involving ll-keto or l2-keto groups, incontradistinction to lactone or ester formation where keto groups areelsewhere in the molecule.

In small quantity reactions and in some solvents such as benzene, thequantity of lactone formed might go unnoticed or be negligible. However,in large scale coinmercial operations, these ll-keto and 12-ketocompounds yield appreciable quantities of lactone, possibly because ofthe increased time element involved. Thus in the perbenzoic acidoxidation of the 3-acetoxy-11,20-diketo-l6- pregnene I, there wasobtained about 40% of the oxide II. About 25-30% of the lactone III isformed and the remaining material is an oil. The oxide II, however, isvery diflicult to purify and the yield, of course, leaves much to bedesired.

ui -Qij It is accordingly an object of the presentinvention to providean improved process for preparing 16,17-oxido- 20-keto steroids of thepregnane series.

A further object is to provide an improved process for preparing16,17-oxido-20-keto pregnenes from pregna-- dienes.

Another object of the invention is to provide a process for preparing16,17-oxido-20-keto compounds of the pregnane series from A -20-ketocompounds of the pregnane series without attack at any points ofisolated unsaturation. v

An additional object is to provide a process for preparing16-,17-oxido-20-keto steroids of the pregnane series which also possessketo groups in the llor 12-positiohs.

Still another object 1s ,to provide a preferential epoxidation procedurefor 20-keto-16-pregnadienes.

Still a further object is to provide novel intermediates in thepreparation of 17a-hydroxy steroids.

Other objects will be apparent from the following description. 7

It has been found that the foregoing objects accomplished by treatmentof the 20-keto-16-pregnene compounds with hydrogen peroxide in alkalinesolution. The reaction results in substantially quantitative formationof the 16,17-oxido compounds without attack at other double bonds notconjugated with a ketogroup and Without formation of lactones fromcyclic ketones. Thus, upon treatment of l6-pregnene-ol-3-one-20 acetate,a quantitative yield of 16,17-oxido-pregnane-ol-3pone-20 was obtained.Treatment of 5,16-pregnadiene-ol- 3 ,B-one-ZO acetate similarly resultsin substantially a quantitative yield of16,17-oxido-5-pregnene-ol-3B-one-20. Treatment of16-pregnene-3a-ol-11,20-dione acetate led to an almost quantitativeyield of 16,17-oxido-pregnane- The following examples are illustrativeof conditions for practicing the invention.

Example 1 16,17-oxido-5-pregnene-3fl-ol-2O-one from5,16-prgnapregnadiene-3fl-ol 20-one acetate in 200 cc. of methanol wastreated at 15 C. with 6 cc. of 4 N. sodium hydroxide Example 216,17-0xid0-5-pregnene-3B-ol-20-one from5,16-pregnadiene-3fl-ol-20-one.-5,16 pregnadiene 3p 01- 20-one, M. P.212-215 C., was treated in much the same manner as described in Example1 for the corresponding acetate. 3.0 g. of the SB-hydroxy compoundyielded 2.4 g. of recrystallized 16,17-oxido-5-pregnene-3B-ol-20-onemelting at 188-190 C.

Example 3 16,17-oxido-pregnane-3a-ol-l1,20-dione from16-pregnene-3a-0l-11-20-dione acetate.-A solution of 8.0 g. of16-pregnene-3a-ol-11,20-dione acetate in 400 cc. of methanol was cooledto 10 C. and treated with 16 cc. of 4 N. sodium hydroxide solution and32 cc. of 30% hydrogen peroxide. The mixture was promptly cooled, andafter forty hours at 2 C., the solution was filtered and concentrated invacuo with little heating to halfvolume. Water was added portionwiseuntil one liter of crystallizing solution was obtained. The crystalswere filtered, washed three times with distilled water and driedyielding 6.8 g. of the oxide of melting point 217-219 C.

For analyses, 21 sample was recrystallized from acetone, which gavewhite plates, M. P. 220 C.

can be This Example 4 Preparation of9(11),I6-pregnadiene-3u-1I-diol-ZO-one 3,11-diacetate.-A solution of10.0 g. of pregnane-3a-ol- 11,20-dione acetate in 450 cc. of aceticanhydride' containing 5.0 g. of p-toluene-sulfonic acid monohydrate wasslowly distilled for a period of twelve hours. During this period, 355cc. of distillate was collected. The dark residual solution wascarefully decomposed with water and extracted with ether. The etherealsolution was washed with water, 2% aqueous sodium hydroxide solution andthen with water. till free of alkali. The dried solution wasconcentrated in vacuo to a tan, crystalline mass. This was taken up inalcohol-free ether and poured over a column of 60 g. of activatedalumina. The desired product was eluted with about 800 cc. of ether.Concentration of the ether eluate and dilution with petroleum ether (B.P. 3560) gave 5.0 g. of 9(1l),17(20)-pregnadiene-3u,11,20-triol3,11-20-triacetate, M. P. 192-198 C. The material contained in themotherliquor proved suit able for recycling.

The 9(11),17(20)-pregnadiene-3a,11,20-triol 3,11,20- triacetate (3.0 g.)was dissolved in 50 cc. of acetic acid and treated with 8.42 cc. of'asolution of bromine in acetic acid (contains 1.05 g. Bra). Aftercomplete decolorization, the product was precipitated with water,filtered and dried. There was obtained 3.1 g. of 17-bromo-9(11)-pregnene-3a,11-diol-20-one 3,11 diacetate.

The 17-bromo compound was dissolved in cc. of collidine and refluxedfor'two hours. The mixture was then diluted with ether, and the etherealmixture washed with water, dilute hydrochloric acid, and Water. Aftertreatment of the ether solution with charcoal and separation of thelatter, the solution was concentrated. The residual material gave uponcrystallization of acetonepetroleum ether (B. P. 3560), 1.17 g. ofmaterial melting at 174-180 C. One recrystallization raised the meltingpoint of the 9(11),16,-pregnadiene-3a,11,diol-20- one 3,1l-diacetate to180-482 C.

' Example 5 16,17 oxido-pregnane 3m ol 11,20 dione from 9(1] ),16pregnadiene 311,11 dial 20-one, 3,11 -diacetare.'A solution of 1.0 g. of9(11),16-pregnadiene-3a,11- diol-20-one 3,11-diacetate in 75 cc. ofmethanol was the invention.

4 treated with 2 cc. of 4 N. sodium hydroxide solution and 4 cc. of 30%hydrogen peroxide solution. This solution was allowed to stand for 40hours at 2 C. It was then concentrated in vacuo to about 25 cc. anddiluted with two volumes of water. After, chilling the plate-likecrystals were separated, washed with water and dried. The dried 16,17oxydopregnane 3a o1 11,20 dione weighed 710 mg. and melted at 218-220 C.

The foregoing examples show that the alkaline hydrogen peroxidetreatment is specific for the conjugated 16-17 unsaturated linkage ofthe conjugated A -20-keto structure, leaving any isolated points ofunsaturation untouched. Thus, neither carbonyl, enol nor carbon-carbondouble bond structures were attacked. Thus by the process compounds alsocontaining non-conjugated car.-

bonyl groups may be treated without lactone or ester formation involvingsuch carbonyl groups. Similarly it is not necessary to protect isolatedcarbon-carbon double bonds by separate procedures against epoxideformation.

It will be apparent that various modifications may be made in theprocedure to be employed. Thus free alcohols instead of esters may beemployed. Other esters than the acetate may also be used withoutdeparting from Thus propionates, butyrates, benzoates, etc. may beemployed in practicing the invention.

It has been previously pointed out that while prior work indicates thatll-keto and 12-keto steroids are resistant to lactone formation ontreatment with perbenzoic acid, our experience has been tothev contrary.Also, Karrer, Organic Chemistry, Eng. Ed. (1938), page 630, states thatcyclic ketones on treatment with hydro gen peroxide are oxidized tolactones. Moreover, Fieser and Fieser, Natural Products Related toPhenanthrene, 3rd ed. (1949), on page 220, show that when cholesterol istreated with acid hydrogen peroxide, a vicinal glycol is formed. Fieserand Fieser also state on page 227 that the or, -unsaturated ketones arenot easily hydroxylated by the usual reagents: perbenzoic acid, hydrogenperoxide or osmium tetroxide. It is thus seen that the instant inventionprovides a distinctly novel and unpredictable procedure for thepreferential epoxidation of A -20-ketopregnenes also possessingnon-conjugated unsaturation elsewhere in the steroid molecule.

Reference is made herein to Serial No. 109,808, filed August 11, 1949,describing and claiming the 16,17-oxide- 20-keto-5-pregnenes disclosedherein.

Having described the invention, what is claimed is:

16,17-oxido-pregnane-3 oc-Ol-l l,20-dione.

No references cited.

1. 16,17-OXIDO-PREGNANE-3A-OL-11,20-DIONE.